It is now a well established fact that a prerequisite for the action of a drug is its ability to penetrate the lipid cell membranes. A substance can act only through its undissociated, lipid soluble part. This sets a limitation for the intravenous administration of compounds with a pK.sub.a value far from the physiological pH range. On the other hand, a drug has to be dissolved in a physiological vehicle, which normally is an isotonic aqueous solution. Thus, many drugs can only be administered orally as tablets or as suspensions, despite the fact that there is a marked therapeutic need for a parenteral route of administration.
The degree of protein binding differs from drug to drug and from species to species. The albumin bound part of a drug may be regarded as a floating depot, but it has no pharmacological effect per se. Repeated administrations sooner or later give a saturation of the albumin binding capacity and finally enough free drug to give a pharmacological effect.
The physiological mechanism of the fat transport in the blood and lymph is by chylomicrons with a median particle diameter between 0.2 and 0.3 .mu.m (range 0.05-0.50 .mu.m) and containing phospholipids and protein in the membrane.
In the administration of pharmacologically active agents, it has up to now mostly been necessary to use water-soluble agents or to transform the agents into a water-soluble form, so that a solution can be obtained having the properties required for the administration. The use of the agents in a water-soluble form, however, has often had several disadvantages. For instance, the aqueous solutions may often be acidic or basic, which may cause side effects. Also, it may sometimes be difficult to attain a desired effect, as the solutions cannot be tolerated by the patient.
It has long been postulated that a higher degree of lipophilisity will support an increased pharmacological action of a pharmacon. In 1937 Meyer said that "Narcosis commences when any chemical indifferent substance has attained a certain molar concentration in the lipids of the cell." Until now, it has been difficult to deny or accept this theory as there was no way to administer these lipophilic and hydrophobic substances so that the pharmacokinetics of the compounds could not be investigated.
It is known from Remington's Pharmaceutical Sciences, 13th Edition, 1965, Page 288, Column 2, Line 23, that "Most stable emulsions have particle sizes in the range of 0.25 to 5.0 microns (.mu.)." However, the reference is to emulsions in general without any appreciation of the utilization of such emulsions for the parenteral administration of oil-soluble pharmacologically active agents, and more specifically there is no appreciation that such emulsions can be utilized as a carrier emulsion to enhance the parenteral administration of oil-soluble pharmacologically active agents whereby a lower dose rate can be utilized than heretofore to achieve a given effect.
U.S. Pat. No. 2,972,565 to Zilversmit discloses fat concentrates for use in the preparation of fat-in-water emulsions when diluted with water and disclosed as suitable for intravenous administration. However, we have made extensive tests in accordance with the examples of the Zilversmit patent, and all tests have ended in failure. Even with the use of modern high-speed emulsifying equipment, it has not been possible to prepare emulsions from Zilversmit's concentrates which have had the small and uniform particle size which is essential in accordance with the present invention. When administering placebo emulsions of this type to mice, up to 50% of the test animals have died. The teachings of the patent to Zilversmit cannot be considered to lead one skilled in the art to the present method of enhancing the parenteral administrations of oil-soluble pharmacologically active agents.